Tuberculosis (TB) is a major public health burden globally. After close contact with a person with pulmonary TB, most people become infected by inhaling aerosolized Mycobacterium tuberculosis (MTB). Most control this infection without eliminating it and develop latent MTB infection (LTBI) as measured by a positive tuberculin skin test (TST) and/or interferon-? release assay (IGRA). In a large TB household contact study in urban Uganda we were surprised to find that 9.1% of close adult household contacts (HHC) remained persistently TST negative during two years of follow-up. The persistently TST negative state suggests that some individuals may either resist and/or rapidly abort MTB infection. Characterization of immune responses in persons resisting MTB infection (RSTR) will enable identification of natural resistance mechanisms to MTB. The epidemiological risk profiles of RSTRs did not differ significantly from HHC who had or developed LTBI. Using microarrays and mRNA isolated from MTB-infected blood-derived monocytes, we identified transcriptional signatures that distinguish RSTR from persons with LTBI. Specifically, using Gene Set Enrichment Analysis and Linear Neural Network analysis, we found that the imatinib-ABL pathway and the COLEC10 gene may distinguishes RSTR from LTBI and thus are either directly involved in or markers of resistance to MTB infection. Using a genome-wide linkage study, we also discovered gene variants in innate immune pathways that distinguished RSTR from persons with LTBI. These result support the hypothesis for this ICIDR that RSTR have protective innate immune responses that are mediated by macrophages. This hypothesis will be tested in 3 aims. Aim1. Determine the long-term stability of the RSTR phenotype and identify elite RSTRs. Determine whether whole blood MTB killing differentiates RSTRs from LTBI individuals. Aim2. Determine the mechanism of how the candidate resistance genes ABL and COLEC10 regulate responses to MTB infection in macrophages from RSTR and LTBI individuals. Aim3. Determine ABL and COLEC10 function and MTB-induced transcriptional signatures in alveolar macrophages that are associated with susceptibility or resistance to MTB infection and validate findings in a new cohort of RSTRs. To accomplish this ICIDR's aims we bring together a multidisciplinary and experienced team of long-term collaborating researchers at Makerere University (Mayanja, Mupere) in Kampala (Uganda), Univ. of Washington (Hawn, Seshadri) and Case Western Reserve University (Boom, Johnson, Stein). This ICIDR project will provide capacity building and training opportunities in clinical and laboratory TB research.